Cyclosporine A Drives a Th17‐and Th2‐Mediated Posttransplant Obliterative Airway Disease
American Journal of Transplantation
Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8+ T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4+ depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.
Lemaître, Phillipe; Vokaer, Benoit; Charbonnier, Louis-Marie; Iwakura, Y.; Field, Ken; Estenne, M.; Goldman, M.; Leo, O.; Remmelink, M.; and Le Moine, Alain. "Cyclosporine A Drives a Th17‐and Th2‐Mediated Posttransplant Obliterative Airway Disease." American Journal of Transplantation (2013) .